Mono-ester and asymmetrically substatuted di-ester pro-drugs of dopamide D1 receptor agonists

ABSTRACT

Mono-ester and asymmetrically substituted diesters of dihydrexidine, dinapsoline and A-86929 and substituted derivatives thereof are described. The novel ester/diester derivatives exhibit improved pharmacokinetic characteristics relative to their unesterified parent compounds and can be formulated into pharmaceutical compositions useful for the treatment of a wide variety of dopamine related disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national counterpart application ofinternational application serial No. PCT/US03/04592 filed Feb. 14, 2003,which claims priority to Swedish Patent Application No. 0200478-6 filedFeb. 15, 2002 and Swedish Patent Application No. 0200474-5 filed Feb.17, 2002. The entireties of each of these applications are herebyincorporated by reference.

FIELD OF THE INVENTION

This invention relates to novel mono-ester and asymmetricallysubstituted di-ester pro-drugs of dopamine D1 receptor agonists, usefulfor treating dopamine-related neurological, psychological,cardiovascular, cognitive and behavioral disorders.

BACKGROUND OF THE INVENTION

Dopamine is an important neurotransmitter in the central nervous system(CNS), as where it is involved with motor function, perception, arousal,motivation and emotion. Dopamine imbalance is believed to play a keyrole in a number of CNS-related disorders such as schizophrenia,Parkinson's disease, drug abuse, eating disorders and depression.Dopamine also has several important roles in the peripheral nervoussystem, such as in the control of blood to the kidneys and inautotonomic ganglion transmission.

Dopamine receptors in the CNS have traditionally been divided into twogeneral categories, designated D-1 and D-2 receptors, based onbiochemical and pharmacological differences between the two receptortypes, and more recently from the study of the molecular biology ofdopamine receptors in the CNS. (For a review of the classification andfunction of dopamine receptor subtypes, see C. Kaiser and T. Jain,“Dopamine Receptors: Functions, Subtypes and Emerging Concepts”,Medicinal Research Reviews, 5:145–229, 1985.) Recent additional evidencehas suggested an even greater heterogeneity of the dopamine receptorswith three additional dopamine receptors being defined through molecularcloning techniques: the D3 and D4, which are classified as D2-like, andthe D5, which exhibits D1 receptor-like pharmacology (D. Sibley and F.Monsma, “Molecular Biology of Dopamine receptors”, in TIPS, Vol. 13, pp.61–69, 1992). Attempts to understand the physiological andpathophysiological roles of the various dopamine receptors arecontinuing to unveil new avenues for novel therapeutic approaches forthe treatment of dopamine-related disorders.

A particular dopamine-related problem involves the loss of striataldopamine within the basal ganglia, the region of the mammalian brainthat is involved with motor control, which has been established as thefundamental deficit in Parkinson's Disease and primary to the etiologyof that disease state.

This deficiency is addressed via dopamine replacement therapy, primarilywith L DOPA (3,4-dihydroxyphenylalanine), which is converted to dopaminewithin the brain. L-DOPA has been the cornerstone of Parkinson's Diseasetherapy, and the successes achieved with its therapy have led to thetesting of other compounds capable of eliciting the post-synapticreceptor actions of dopamine.

Bromocriptine, the most widely used direct-acting dopamine agonist forthe treatment of Parkinson's Disease, is administered adjunctively withL-DOPA in order to lower dosage of L-DOPA required to achieve thedesired therapeutic response. Bromocriptine alone has been shown torelieve Parkinson's Disease symptoms in some patients, allowing for adelay in the onset of L-DOPA therapy, but the response to bromocriptinealone is not as great as that observed with L DOPA. The currenttherapies for Parkinson's Disease, including L-DOPA and bromocriptine,are, however, unfortunately associated with a number of seriousside-effects and limitations, such as the development of dyskinesias,severe response fluctuations (on-off phenomenon) and diminishingefficacy during treatment.

An excess of dopamine in the brain, on the other hand, has beanidentified, as a result of the pioneering work of Carlsson and others inthe 1960's, as the cause of schizophrenia, a psychiatric illnessinvolving disturbance of thought processes, hallucinations and loss oftouch with reality. Chronic abuse of stimulants, such as amphetamines,known to enhance dopaminergic activity in the brain, can lead to aparanoid psychosis that is clinically indistinguishable from classicparanoid schizophrenia, further supporting this dopamine theory ofschizophrenia.

Anti-schizophrenic drugs are postulated to exert their effects byblocking the dopamine receptors (i.e., acting as receptor antagonists),and consequently preventing excess receptor stimulation (G. P. Reynolds,“Developments in the drug treatment of schizophrenia”, in TIPS,:116–121, 1992). These antipsychotic agents frequently produceundesirable side-effects, however, the most common of which are theextrapyramidal effects that include bizarre involuntary movements andParkinson-like states, as well as sedation and hypotension. Because ofthese often severe side-effects and the high incidence of patientsunresponsive to dopamine blocking drugs, novel and improved therapiescontinue to be sought.

One such complement to dopamine receptor antagonists has included theuse of low doses of dopamine agonists, such as apomorphine andbromocriptine. which have been reported to produce anti psychoticeffects, possibly due to preferential activation of dopamine presynapticreceptors resulting in decreased dopaminergic activity (M. Del Zompo etal, “Dopamine agonists in the treatment of schizophrenia”, Progress inBrain Research, E:41–48, 1986 end H. Y. Meltzer, “Novel Approaches tothe Pharmacology of Schizophrenia”, Drug Development Research, 9:23–40,1986). In addition, the dopamine D1-selective agonist, SKF 38393, whenused in conjunction with the antipsychotic drug, haloperidol, a D2antagonist, has been shown to ameliorate the undesired side-effects ofthe haloperidol (M. Davidson, “Effects of the D-1 Agonist SKF-38393Combined With Haloperidol in Schizophrenic Patients”, Arch Gen.Psychiatry, 42:190–191, 1990).

Growing evidence (reviewed by R. A. Wise and P. P. Rompre in “BrainDopamine and Reward”, Annual Review of Psychology, 40:191–225, 1989)suggests that dopamine also has a central role in the brain's rewardsystem. For example, animals trained to self-administer cocaine willincrease their consumption of this drug after treatment with either aD-1 or a D-2 receptor antagonist, presumably in order to maintain theelevated dopamine levels responsible for the drug's euphorigenic andreinforcing properties (D. R. Britten et al, “Evidence for Involvementof Both D1 and D2 Receptors in Maintaining Cocaine Self-Administration”,Pharmacology Biochemistry & Behavior, 89:911–915, 1991). The D-1agonist, SKE 38393, has also been reported to decrease food intake byrats, presumably by direct action of the drug on neural feedingmechanisms. Because of this interrelationship between dopamine andreward, dopaminergic agents would be useful for the treatment ofsubstance abuse and other addictive behavior disorders, includingcocaine addiction, nicotine addiction and eating disorders.

Affective disorders, the most common psychiatric disorders in adults,which are characterized by changes in mood as the primary clinicalmanifestation, result from a reduction in the central nervous system ofcertain biogenic amine neurotransmitters, such as dopamine,noradrenaline and serotonin. Currently available antidepressants workprimarily by raising biogenic amine neurotransmitter levels, by eitherinhibiting their uptake or preventing their metabolism. Noantidepressant drug to date, however, can substitute forelectroconvulsive shack therapy for the treatment of severe, suicidaldepression.

Currently-available drugs for treating affective disorders,unfortunately, suffer from delayed onset of action, poor efficacy,anticholinergic effects at therapeutic doses, cardiotoxicity,convulsions and the possibility of overdosing. A large number ofclinically depressed individuals remain refractory tocurrently-available therapies.

A role for direct-acting dopamine agonists in antidepressant therapy hasbeen suggested based on the effects observed for several dopamineagonists In various animal models (R. Muscat et al.,“Antidepressant-like effects of dopamine agonists in an animal model ofdepression”, Biological Psychiatry, 31:937–946, 1992).

A role for dopamine has also been established in cognition and attentionmechanisms. Animal studies support the role of dopamine inattention-related behaviors involving search and exploratory activity,distractibility, response rate, discriminability and the switching ofattention. Treatment of cognitive impairment and attention deficitdisorders via dopamine-based therapy has been proposed and is underactive investigation (F. Levy, “The Dopamine Theory of Attention DeficitHyperactivity Disorder (ADHD)”, in Australian and New Zealand Journal ofPsychiatry, 2:277–283, 1991).

In addition, dopamine has been identified with a number of effects inthe periphery, and has been used in the treatment of shock, congestiveheart failure and acute renal failure. Stimulation of the peripheral D-1receptors causes vasodilation, particularly in the renal arid mesentericvascular beds where large numbers of these receptors are found. Theutility of dopamine has been limited, however, by its ability to causevasoconstriction at higher concentrations, presumably due to itssecondary effects on adrenergic receptors, and by its emetic effects dueto peripheral D-2 stimulation. Agents selective for the peripheral D-1receptors appear to offer significant advantages over currently usedtreatments for these and other related disorders.

Also, dopamine in combination with diuretics has been reported toreverse radio-contrast media-induced acute renal failure in patients(Talley at al., Clin. Res., 18:518, 1970); thus suggesting that dopamineagonists may be similarly useful.

A wide variety of structures has been disclosed that are dopaminereceptor ligands (H. E. Katerinopoulos and D. I. Schuster,“Structure-Activity Relationships for Dopamine Analogs A Review”, inDrugs Of The Future, Vol. 12, pp. 223–253, 1987) and include thethienopyridines, SKF 86926 (4-(3′,4′-dihydroxyphenyl)4,5,6,7-tetrahydrotheno (2,3-c)-pyridine) and SKF 86915(7-(3′,4′dihydroxyphenyl)-4,5,6,7-tetrahydrothlieno (3,2-c)-pyridine)(P. H. Andersen et al, European Journal of Pharmacology, 137:291–292,1987, U.S. Pat. No. 4,340,600, to L. M. Brenner and J. R. Wardell, Jr.,issued 1982, and U.S. Pat No. 4,282,227, to L. M. Brenner, issued 1981).Nichols at al. have disclosed certain substitutedtrans-hexahydrobenzo[a]-phenanthridine compounds as dopaminergic ligands(U.S. Pat. No. 5,047,536, to D. E. Nichols, issued 1991; W. K. Brewsteral., “trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: A HighlyPotent Selective Dopamine D1 Full Agonist”, in Journal of MedicinalChemistry, D:1756-1784, 1990).

U.S. Pat. Nos. 5,047,536 and 6,194,423, incorporated herein, describeand claim the dopamine D1 agonists dihydrexidine (Formula I) anddinapsoline (Formula II) and their optionally substituted derivatives,respectively. PCT/US94/02894 describes the dopamine D-1 agonist A-86929(Formula III), its diacylated derivated form (Formula IV) and otheroptionally substituted derivatives of A-86929. For the purpose ofdescribing and specifying this invention, Formulas I–III shall berepresentative of dihydrexidine, dinapsoline, A-86929, respectively, andthe various N- and C- substituted derivatives thereof described in theabove-mentioned patent literature.

Each of the “parent” compounds (R₁═R₂═H) of Formulas I–III and their D-1receptor agonist substituted derivatives/analogs share a commonstructural feature: adjacent phenolic hydroxy groups. The presentinvention is directed to monoester and asymmetrically substituteddiester derivatives of such compounds and their receptor agonistsubstituted derivatives and analogs, where either one of the hydroxygroups is acylated with an ester-forming group or each of the adjacentphenolic hydroxy groups is acylated with a different ester-forminggroup. The compounds of the present invention exhibit unexpectedlyimproved pharmacokinetic properties, as compared to the previousdescribed unacylated “parent” compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to mono-ester and asymmetricallysubstituted di-ester pro-drugs of the dopamine D1 agonists of FormulasI, II and III above and their optionally substituted derivatives whereinone of R₁ and R₂ is hydrogen or acetyl and the other one is selectedfrom the group consisting of (C₃–C₂₀) alkanoyl; halo-(C₃–C₂₀)alkanoyl;(C₃–C₂₀)alkenoyl; (C₄–C₇)cycloalkanoyl;(C₃–C₆)cycloalkyl(C₂–C₁₆)alkanoyl; aroyl which is unsubstituted orsubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, cyano, trifluoromethanesulphonyloxy, (C₁–C₃)alkyl and(C₁–C₃)alkoxy, which latter may in turn be substituted by 1 to 3 halogenatoms; aryl (C₂–C₁₆)alkanoyl which is unsubstituted or substituted inthe aryl moiety by 1 to 3 substituents selected from the groupconsisting of halogen, (C₁–C₃)alkyl and (C₁–C₃)alkoxy, which latter mayin turn be substituted by 1 to 3 halogen atoms; and hetero-arylalkanoylhaving one to three heteroatoms selected from O, S and N in theheteroaryl moiety and 2 to 10 carbon atoms in the alkanoyl moiety andwhich is unsubstituted or substituted in the heteroaryl moiety by 1 to 3substituents selected from the group consisting of halogen, cyano,trifluoromethanesulphonyloxy, (C₁–C₃)alkyl, and (C₁–C₃)alkoxy, whichlatter may in turn be substituted by 1 to 3 halogen atoms, and thephysiologically acceptable salts thereof.

According to one embodiment of the present invention there is provided acompound for Formula I, II or III above or their optionally substitutedderivatives, wherein one of R₁ and R₂ is hydrogen or acetyl and theother one is selected from the group consisting of (C₃–C₂₀)alkanoyl,(C₄–C₇)cycloalkanoyl, benzoyl which is unsubstituted or substituted by achlorine atom or 1 to 3 methoxy groups, phenylacetyl which may besubstituted with a chlorine atom, and heteroarylacetyl.

According to another embodiment of the present invention there isprovided a compound of the general Formulas I, II or III above or theirsubstituted derivatives, wherein one of R₁ and R₂ is hydrogen and theother is selected from the group consisting of propanoyl, propenoyl,butanoyl, isobutanoyl, pivaloyl, decanoyl, hexadecanoyl, cyclopropanoyland benzoyl.

According to another embodiment of the present invention there isprovided a compound of the Formulas I and II or III or their substitutedderivatives, wherein one of R₁ and R₂ is acetyl and the other isselected from the group consisting of butanoyl, isobutanoyl,cyclopropanoyl, cyclohexanoyl, pivaloyl, decanoyl and hexadecanoyl.

With regard to the definition of R₁ and R₂ in Formulas I and II and IIIabove, the following meanings generally apply:

The terms “halo” and “halogen” are used to designate fluorine, chlorine,bromine and iodine, preferably fluorine and chlorine.

The term “(C₃–C₂₀)alkanoyl” is used to designate the residue of asaturated aliphatic carboxylic acid of 3 to 20 carbon atoms, the carbonchain of which may be straight or branched. Examples of such alkanoylgroups are e.g. propanoyl, isopropanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methyl-butanoyl, pivaloyl, n-hexanoyl, n-heptanoyl,n-octanoyl, n-nonanoyl, n-decanoyl, palmitoyl, stearoyl and eicosanoyl.

The term “halo-(C₃–C₂₀)alkanoyl” is used to designate a (C₃–C₂₀)alkanoyl group as defined above which is substituted by at least onehalogen atom, preferably by 1 to 3 halogen atoms.

The term “(C₃–C₂₀)alkenoyl” is used to designate the residue of analiphatic carboxylic acid of 3 to 20 carbon atoms, the carbon chain ofwhich may be straight or branched and which contains 1 to 3 conjugatedor non-conjugated double-bonds. Examples of such alkenoyl groups are,e.g. acryloyl, methacryloyl, linoleoyl and linolenoyl.

The term “(C₄–C₇)cycloalkanoyl” is used to designate a group having theformula

wherein n is an integer 1 to 4.

Such groups include cyclopropanoyl, cyclobutanoyl, cyclopentanoyl andcyclohexanoyl.

The term “(C₃–C₆)cycloalkyl–(C₂–C₁₆)alkanoyl” is used to designate agroup having the formula

wherein n is defined as above, n1 is an integer 1 to 15, and thealkylene chain (C_(n1)H_(2n1)) may be straight or branched. Examples ofsuch groups are, e.g. cyclopropyl acetyl, cyclohexyl acetyl, cyclopropylhexanoyl and cyclopropyl palmitoyl.

The term “aroyl” is used to designate, for example, benzoyl, 1-naphthoyland 2-naphthoyl. Said aroyl group is unsubstituted or substituted by 1to 3 substituents selected from the group consisting of halogen, cyano,trifluoromethanesulphonyloxy, (C₁–C₃)-alkyl and (C₁–C₃)alkoxy, whichalkyl and alkoxy groups in turn may be substituted by 1 to 3 halogenatoms. Examples of such substituted aroyl groups are m-methoxybenzoyl,p-trifuoromethoxybenzoyl. p-chlorobenzoyl, 3,4,5-trimethoxybenzoyl,p-cyanobenzoyl and 3-chloro-1-napthoyl.

The term “(C₁–C₃)alkyl” is used to designate methyl, ethyl, propyl andisopropyl and the term “(C₁–C₃)alkoxy” is used to designate methoxy,ethoxy, propoxy and isopropoxy.

The term “aryl-(C₂–C₁₆)alkanoyl” is used to designate a group of theformula

wherein Aryl and n₁ are as previously defined and the alkylene chain(C_(n1)H_(2n1)) may be straight or branched. The aryl moiety of saidgroup may be substituted with substituents as indicated in connectionwith the aroyl groups above. Examples of aryl-(C₂–C₁₆)alkanoyl groupsare phenacetyl. p-chlorophenacetyl, p-trifluoromethoxyphenylacetyl andphenylhexanoyl.

Examples of hetero-arylalkanoyl groups having one to three heteroatomsselected from O, S and N in the hetero-aryl moiety and 2 to 10 carbonatoms in the alkanoyl moiety and which are unsubstituted or substitutedin the hetero-aryl moiety as indicated above are thiophen-2-yl-acetyland pyrid-4-yl-hexanoyl.

The term “(C₁–C₄)alkyl” is used to designate a straight or branchedalkyl group of 1 to 4 carbon atoms including methyl, ethyl, propyl,isopropyl, butyl, 1-methyl propyl, 2-methyl propyl and t-butyl.

According to another aspect of the invention there are provided methodsfor the preparation of compounds of Formulas I, II and III above andtheir optionally substituted derivatives.

Accordingly, in one method embodiment, there is provided a process forthe preparation of a mono-ester derivative of Formula I, II or III andderivatives thereof:

a) reacting a compound of Formula I, II or m (or a derivative thereof)with an acid chloride of the general formula:R ₄—Cl

wherein R₄ is as defined for said other one of R₁ and R₂ above, in themolar ratio of the compound to acid chloride of from 1:1 to 1:5 and intrifluoracetic acid and methylene chloride (CH₂Cl₂);

b) after the reaction being completed, evaporating the solvents orlyophilizing the reaction mixture;

c) dissolving the residual crude product mixture in CH₂Cl₂ and purifyingby chromatography on Al₂O₃ eluting with CH₂Cl₂ and then witht-BuOH:CH₂Cl₂ or EtOH:CH₂Cl₂ mixtures in a stepwise gradient ofincreasing concentration of t-BuOH and EtOH. respectively, of from 1 to15% by volume, preferably from 2 to 10% by volume, of the mixture, andisolating fractions containing the isomeric mono-ester derivatives and

d) optionally but preferably separating said isomeric mono-esterderivative products known techniques.

According to the present invention there is also provided a process forthe preparation of di-ester derivatives of compounds of the generalFormula I, II and III (or substituted derivatives thereof) wherein oneof R₁ and R₂ is acetyl and the other one is selected from the groupconsisting of (C₃–C₂₀)alkanoyl; halo-(C₃–C₂₀)alkanoyl; (C₃–C₂₀)alkenoyl:(C₄–C₇)cycloalkanoyl; (C₃C₆)-cycloalkyl(C₂C₁₆)alkanoyl; aroyl which isunsubstituted or substituted by 1 to 5 substituents selected from thegroup consisting of halogen, cyano, trifluoromethanesulphonyloxy,(C₁–C₃)alkyl and (C₁–C₃)alkoxy, which latter may in turn be substitutedby 1 to 3 halogen atoms; aryl(C₂–C₁₆)alkanoyl which is unsubstituted orsubstituted in the aryl moiety by 1 to 3 substituents selected from thegroup consisting of halogen, (C₁–C₃)alkyl and (C₁–C₃)alkoxy, whichlatter may in turn be substituted by 1 to 3 halogen atoms; and

hetero-arylalkanoyl having one to three heteroatoms selected from O, Sand N in the heteroaryl moiety and 2 to 10 carbon atoms in the alkanoylmoiety and which is unsubstituted or substituted in the heteroarylmoiety by 1 to 3 substituents selected from the group consisting ofhalogen, cyano, trifluoromethanesulphonyloxy, (C₁–C₃)alkyl, and(C₁–C₃)alkoxy, which latter may in turn be substituted by 1 to 3 halogenatoms; which process comprises

a) reacting a mono-ester of one of the compounds of Formula I, II orIII, wherein

one of R₁ and R₂ is hydrogen and the other one is acetyl with an acidchloride of the general formula:

R ₅—Cl

wherein R₅ is as defined for said other one of R₁ and R₂ above, in themolar ratio of mono-ester to acid chloride of from 1:1 to 1:5 andtrifluoroacetic acid and methylene chloride (CH₂Cl₂);

b) after the reaction being completed, evaporating the solvents orlyophilizing the reaction mixture;

c) dissolving the residual crude product mixture in CH₂Cl₂ and purifyingby chromatography on Al₂O₃ eluting with CH₂Cl₂ and then witht-BuOH:CH₂Cl₂ or EtOH:CH₂Cl₂ mixtures in a stepwise gradient ofincreasing concentration of t-BuOH and EtOH, respectively, of from 1 to16% by volume, preferably from 2 to 10% by volume, of the mixture, andisolating fractions containing the isomeric di-ester derivatives of theformula (1); and

d) optionally, but preferably separating said isomeric di-esterderivatives by known techniques to isolate a single di-ester.

In a first modification of the method for the preparation of a di-esterderivative, a mono-ester of a compound of Formula I, II or m, wherein R₁and R₂ are as defined above except that neither thereof is acetyl, isreacted with acetyl chloride in step a) in the molar ratio of mono-esterto acetyl chloride of from 1:1 to 1:6 and trifluoroacetic acid andmethylene chloride (CH₂Cl₂), whereafter steps b) to d) as above follows.

In another modification of the method for the preparation of a di-esterderivative of Formula I, II or III or a substituted derivative thereof,a mono-ester wherein R₁ and R₂ are as defined above except that neitherthereof is acetyl, is reacted in step a) with acetic acid anhydride inCH₂Cl₂ in the presence of a basic catalyst such as triethylamine orpyridine whereafter steps b) to d) as above follows.

Alternatively, a mono-acetyl ester is reacted with the anhydride of anacid of the formulaR ₅—OHwherein R₅ is as defined above, in a step a) in CH₂Cl₂ in the presenceof a basic s catalyst such as triethylamine or pyridine whereafter stepsb) to d) as above follows.

Catechols, are very sensitive to oxidation (e.g. in atmospheric air).This is especially true under basic conditions. It is thus virtuallyimpossible to handle such catechols in the free base form, without theaddition of antioxidants.

In addition, the pro-drugs of the present invention are designed to beeasily hydrolyzed, making it difficult to use SiO₂ and nucleophilicalcohols for purification of the esters of the invention via columnchromatography.

In step a) of the processes according to the present invention theesterification, for example of dihydrexidine or dinapsoline or itsmono-acetyl ester, respectively, is performed under acidic conditions intrifluoroacetic acid (CF₃COOH) diluted with methylene chloride (CH₂Cl₂),a suitable dilution ratio being about 3–10 times. The acid chloride,possibly dissolved in CH₂Cl₂, is added to dihydrexidine or dinapsolineor its mono-acetyl ester, respectively, at a molar ratio betweendihydrexidine or dinapsoline or its respective mono-ester to acidchloride of from 1:1 to 1:5. The optimal ratio will vary depending onthe steric properties of the acid chloride but will generally be withinthe range of from 1:1 to 1:2.

The reaction can be monitored by means of thin layer chromatography(Al₂O₃ and eluting with CH₂Cl₂ or CH₂Cl₂:t-BuOH mixtures or CH₂Cl₂:EtOHmixtures).

After the reaction has become complete (generally within 1–24 h,depending on the acid chloride and molar ratio used) the solvents areevaporated from the reaction mixture or the reaction mixture islyophilized in step b) of the processes of the invention. Evaporation ofthe solvents is generally carried out under reduced pressure.

For purification according to step c) of the processes of the presentinvention the residual crude product mixture from step b) is, in step c)dissolved in CH₂Cl₂ and purified, for example, by chromatography onAl₂O₃, elution being carried out by using first CH₂Cl₂ and then withmixtures of t-BuOH and CH₂Cl₂ in a stepwise gradient of increasingconcentration of t-BuOH of from 1 to 15% by volume of t-BuOH calculatedon the mixture, preferably from 2 to 10% by volume, for instance insteps of 1.0, 2.0, 5.0 and 10%. During the elution fractions containingthe desired isomeric ester derivatives are collected.

The isomeric mono-esters may then be separated using known techniquessuch as flash chromatography, preparative HPLC (High Performance LiquidChromatography), crystallization and other methods known per se.However, some of the isomeric mono-esters may prove difficult toseparate and in such a case the mixture of the two isomers may be usedas the starting material for the preparation of asymmetric di-esters oras the active principle in a pharmaceutical preparation.

In case of the preparation of the asymmetric di-esters, starting from anindividual mono-ester isomer, the asymmetric di-esters will typicallyelute first and unreacted mono-esters thereafter.

Also in this case, when starting from a mixture of the two possibleisomers of the mono-ester resulting from the esterification process ofthe present invention, the two di-ester isomers may prove difficult toseparate and so it may appear advantageous to use the mixture of isomersas the active principle in a pharmaceutical preparation rather thantaking the cost for the separation of the isomers.

According to a further aspect of the present invention there is provideda pharmaceutical composition comprising, as an active principle, atleast one mono-ester or asymmetric di-ester of a compound of Formulas I,II and III as defined above (including optionally substitutedderivatives) or a physiologically acceptable salt thereof together witha pharmaceutically acceptable carrier, diluent or excipient.

The term “at least one” as used in the paragraph next above is primarilymeant to refer to the case when the mixture of two isomers resultingfrom the esterification process of the present invention is difficult toseparate and hence it might appear advantageous to use said mixturerather than a single isomer. It might also appear advantageous to usethe mixture of the two isomers or a combination of two compoundsaccording to the invention having different combinations of the meaningsof the symbols R₁ and R₂ in Formulas I, II and III between each other.

The ester pro-drugs of Formulas I, II and III and their optionallysubstituted derivatives, according to the invention may be incorporatedin the pharmaceutical composition according to the invention as the baseor as an acid addition salt, especially the hydrochloride salt. Othersuitable salts are those formed by the acids HBr and sulphonic acidslike methanesulphonic acid, octanesulphonic acid and hexadecansulphonicacid.

The term “administration” of the dopaminergic agent or composition, asused herein, refers to systemic use, as when taken orally, parenterally,by inhalation spray, by nasal, rectal or buccal routes, or topically indosage form unit formulations containing conventional nontoxicpharmaceutically-acceptable carriers, adjuvants and vehicles, asdesired.

The term “parenteral” as used herein includes intravenous,intramuscular, intraperitoneal, intrastemal, subcutaneous andintraarticular injection and infusion techniques.

By “pharmaceutically-acceptable” is meant those salts and esters, whichare within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio, effective for theirintended use in the treatment of psychological, neurological,cardiovascular and addictive behavior disorders.

As used herein, the term “pharmaceutically-acceptable carriers” means anontoxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of the materials that can serve as pharmaceutically-acceptablecarriers are sugars, such as lactose, glucose and sucrose: starches,such as corn starch and potato starch; cellulose and its derivatives,such as sodium carboxymethyl cellulose, ethyl cellulose and celluloseacetate; powdered tragacanth; malt; gelatin; talc; excipients, such ascocoa butter and suppository waxes; oils, such as peanut oil, cottonseedoil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;glycols, such as propylene glycol; polyols, such as glycerin, sorbitol,mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyllaurate; agar; buffering agents, such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline;Ringers solution; ethyl alcohol and phosphate buffer solutions, as wellas other non-toxic compatible substances used in pharmaceuticalformulations. Wetting agents, emulsifiers and lubricants, such as sodiumlauryl sulfate and magnesium stearate, as well as coloring agents,releasing agents, coating agents, sweetening, flavoring and perfumingagents, preservatives and antioxidants can also be present in thecomposition, according to the judgment of the formulator. Examples ofpharmaceutically-acceptable antioxidants include water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfite, sodium metabisulfite, sodium sulfite, and the like; oilsoluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol and the like; and the metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid and the like.

By a “therapeutically-effective amount” of a dopaminergic agent is meanta sufficient amount of the compound to treat dopamine-related disordersat a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically-effective dose level for any particular patientwill depend upon a variety of factors, including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, gender and diet of the patient: the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidentally with the specific compound employed; andlike factors well known in the medical arts.

The term “affective disorder” as used herein refers to disorders thatare characterized by changes in mood as the primary clinicalmanifestation, for example, depression.

The term “anti psychotic agent” as used herein refers to drugs usedextensively in the symptomatic management of all forms of schizophrenia,organic psychosis, the manic phase of manic depressive illness and otheracute idiopathic illnesses and occasionally used in depression or insevere anxiety.

The term “attention deficit disorder” refers to a recently-classifiedpediatric neuropsychiatric disorder characterized by inattention,impulsivity, distractibility and sometimes hyperactivity, which replacesthe less formal diagnoses of hyperactivity syndrome, hyperkineticsyndrome, minimal brain dysfunction and specific learning disability.The disorder is prevalent among pre-adolescent children and is reflectedin poor school performance and social behavior and has been described inexperimental reports of impaired perceptual, cognitive and motorfunction.

The term “cognitive impairment” refers to a deficiency in any of theaspects of the is cognitive (information processing) functions ofperceiving, thinking and remembering.

The term “dopamine-related cardiovascular disorders” as used hereinrefers to conditions which can be reversed or improved by administrationof dopamine or a dopaminergic agent, either alone or in combinationtherapy with other classes of cardiovascular agents. The usefulness ofdopaminergic agents in cardiovascular diseases, for example in thetreatment of shock and congestive heart failure, is based on the known,but incompletely understood, role of dopamine in the cardiovascularsystem, especially the effects of dopamine on the heart and the abilityof dopamine to produce vasoconstriction while maintaining blood flowthrough renal and mesenteric beds. Also included are other related,potential uses for dopaminergic agents which include, for example, usein renal failure.

The term “dopamine-related neurological and psychological disorders” asused herein refers to behavioral disorders, such as psychoses andaddictive behavior disorders; affective disorders, such as majordepression; and movement disorders, such as Parkinson's Disease,Huntington's Disease and Gilles de la Tourette's syndrome; which havebeen linked, pharmacologically and/or clinically, to either insufficientor excessive functional dopaminergic activity In the CNS. Also includedare miscellaneous indications for which dopaminergic agents have beenfound to be clinically useful. Examples of such indications includedisorders characterized by vomiting, such as uremia, gastroenteritis,carcinomatosis, radiation sickness, and emesis caused by a variety ofdrugs; intractable hiccough and alcoholic hallucinosis.

“Normal dopamine levels” are those levels of dopamine that are found inthe brains of control subjects and are usually measured as levels of thedopamine metabolites homovanillic acid (3-methoxy-4-hydroxphenylaceticacid) and 3,4-dihydroxyphenylacetic acid. Abnormal dopamine levels arethose levels that are not within the range of dopamine levels found inthe brains of control subjects.

The term “substance abuse” is used herein to mean periodic or regularself-administration of psychoactive substances in the absence of medicalindications and despite the presence of persistent or recurrent social,occupational, psychological or physical problems that the person knowsare caused by or may be exacerbated by continued use of the substance.

The total daily dose of the compounds of this invention administered toa host in single or in divided doses may be in amounts, for example,from 0.01 to 50 mg/kg body weight or more, usually from 0.1 to 30 mg/kgbody weight Single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose. In general, treatmentregimens according to the present invention comprise administration to apatient in need of such treatment from about 10 mg to about 1000 mg ofthe compound(s) of this invention per day in multiple doses or in asingle dose.

The compounds of the present invention may be administered alone or incombination or in concurrent therapy with other agents which affect thedopaminergic system, for example, L-dopa, amantadine, apomorphine orbromocryptine; and with cholinergic agents, for example, benztropine,biperiden, ethopromazine, procyclidine, trihexylphenidyl, and the like.The compounds of the present invention may also be co-administered withagents, for example, enzyme inhibitors, which block their metabolictransformation outside the CNS.

This invention also provides pharmaceutical compositions in unit dosageforms, comprising a therapeutically-effective amount of a compound (orcompounds) of this invention in combination with a conventionalpharmaceutical carrier.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringers solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil may beemployed, including synthetic mono- or diglycerides. Also, fatty acids,such as oleic acid, are used in the preparation of injectables.

The injectable formulation may be sterilized, for example, by filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which may be dissolvedor dispersed in sterile water or other sterile injectable medium lustprior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of a drug from subcutaneous or intramuscular injection.The most common way to accomplish this is to inject a suspension of thedrug in a crystalline or amorphous material which has poor watersolubility The rate of absorption of the drug becomes dependent on therate of dissolution of the drug which is, in turn, dependent on thephysical state of the drug, for example, the crystal size of the drugand its crystalline form. Another approach to delaying absorption of adrug is to administer the drug as a solution or suspension in oil.

Injectable depot forms may also be made by forming microcapsule matricesof drugs and biodegradable polymers, such as withpolylactidle-polyglycolide.

Depending on the ratio of drug to polymer and the composition of thepolymer, the rate of drug release may be controlled by this method.Examples of other biodegradable polymers include poly-orthoesters andpolyanhydrides. The depot injectables can also be made by entrapping thedrug in liposomes or microemulsions which are compatible with bodytissues.

Suppositories for rectal administration of the drug may be prepared bymixing the drug with a suitable non irritating excipient, such as cocoabutter and polyethylene glycol, both of which are solid at ordinarytemperature, but liquid at the rectal temperature and will thereforemelt in the rectum, releasing the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, pills and granules. In such solid dosage formsthe active compound may be admixed with at least one inert diluent, suchas sucrose, lactose or starch., such dosage forms may also comprise, asis normal practice, additional substances other than inert diluents,e.g., tableting lubricants and other tableting aids, such as magnesiumstearate and microcrystalline cellulose.

In the case of capsules, tablets and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills may additionally beprepared with enteric coatings and other release-controlling coatings.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar, as well as high molecular weight polyethylene glycols andthe like.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs containing inert diluents commonly used in the art, such aswater, such compositions may also comprise adjuvants, such as wellingagents: emulsifying and suspending agents; sweetening, flavoring andperfuming agents.

If desired, the compounds of the present invention can be incorporatedinto slow release or targeted-delivery systems, such as polymermatrices, liposomes and microspheres.

The active compounds may also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules may be prepared with coatings andshells, such as enteric coatings and other coatings well-known in thepharmaceutical formulating art. They may optionally contain opacifyingagents, and may also be of a composition that they release the activeingredient(s) only, or preferably, in a certain part of the intestinaltract, optionally In a delayed manner. Examples of embeddingcompositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention further include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or transdermal patches. The activecomponent is admixed under sterile conditions with apharmaceutically-acceptable carrier and any needed preservatives orbuffers, as required. Ophthalmic formulations, ear drops, eye ointments,powders and solutions are also contemplated as being within the scope ofthis invention. Administration sublingually, from one or more of theabove dosage forms, is also contemplated as a suitable mode ofadministration of the compounds of the invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to the compounds of thisinvention, excipients, such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays may additionally contain customary propellants, suchas chlorofluorohydrocarbons or environmentally- andpharmaceutically-acceptable substitutes.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms may be made bydissolving or dispersing the compound in the proper medium. Absorptionenhancers may also be used to increase the flux of the compound acrossthe skin. The rate may be controlled by either providing arate-controlling membrane or by dispersing the compound in a polymermatrix or gel.

1. A mono-ester or asymmetrically substituted di-ester pro-drug of adopamine D₁ agonist selected from the following formulas:

wherein one of R₁ and R₂ is hydrogen or acetyl and the other one isselected from the group consisting of (C₃–C2)alkanoyl;halo-(C₃–C₂₀)alkanoyl; (C₃–C₂₀)alkenoyl; (C₄–C7)cycloalkanoyl;(C₃–C6)-cycloalkyl(C₂–C₁₆)alkanoyl; aroyl which is unsubstituted orsubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, cyano, trifluoromethanesulphonyloxy, (C₁–C₃)alkyl, and(C₁–C₃)alkoxy, which latter may in turn be substituted by 1 to 3 halogenatoms; aryl(C₂–C₁₆)alkanoyl which is unsubstituted or substituted in thearyl moiety by 1 to 3 substituents selected from the group consisting ofhalogen, (C₁–C₃)alkyl, and (C₁–C₃)alkoxy, which latter may in turn besubstituted by 1 to 3 halogen atoms; and hetero-arylalkanoyl having oneto three heteroatoms selected from oxygen, sulfur, and nitrogen in theheteroaryl moiety and 2 to 10 carbon atoms in the ailcanoyl moiety andwhich is unsubstituted or substituted in the heteroaryl moiety by 1 to 3substituents selected from the group consisting of halogen, cyano,trifluoromethanesulphonyloxy, (C₁–C₃)alkyl, and (C₁–C₃)alkoxy, whichlatter may in turn be substituted by 1 to 3 halogen atoms, and thephysiologically acceptable salts thereof; providing that in Formula I,when one of R₁ and R₂ is hydrogen, the other one of R₁ and R₂ is notpivaloyl or benzoyl.
 2. A compound of Formula I, wherein R₁ is acetyland R₂ is pivaloyl.
 3. A compound of Formula I, wherein R₂ is acetyl andR₁ is pivaloyl.
 4. A compound of Formula II, wherein R₁ is hydrogen oracetyl and R₂ is pivaloyl.
 5. A compound of Formula II, wherein R₂ ishydrogen or acetyl and R₁ is pivaloyl.
 6. A compound of Formula III,wherein R₁ is hydrogen or acetyl and R₂ is pivaloyl.
 7. A compound ofFormula III, wherein R₂ is hydrogen or acetyl and R₁ is pivaloyl.
 8. Apharmaceutical composition for selectively binding and activatingdopaminergic D₁ receptors, said pharmaceutical composition comprising apharmaceutically-acceptable carrier and a compound according to claim 1in an amount sufficient to activate dopamine D₁ receptors.
 9. Apharmaceutical composition for treating Parkinson's disease,characterized by abnormal dopaminergic activity and responsive toactivation of dopamine D₁ receptors, said pharmaceutical compositioncomprising a pharmaceutically-acceptable carrier and an amount of acompound of claim 1 sufficient to activate dopamine D₁ receptors.
 10. Amethod for treating Parkinson's disease, characterized by abnormaldopaminergic activity and responsive to activation of dopamine D₁receptors, said method comprising the step of administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim 1.